@article{7fa4dec281dd4f1496a4247ccf40ae89,
title = "The Drug Rediscovery protocol facilitates the expanded use of existing anticancer drugs",
abstract = "The large-scale genetic profiling of tumours can identify potentially actionable molecular variants for which approved anticancer drugs are available(1-3). However, when patients with such variants are treated with drugs outside of their approved label, successes and failures of targeted therapy are not systematically collected or shared. We therefore initiated the Drug Rediscovery protocol, an adaptive, precision-oncology trial that aims to identify signals of activity in cohorts of patients, with defined tumour types and molecular variants, who are being treated with anticancer drugs outside of their approved label. To be eligible for the trial, patients have to have exhausted or declined standard therapies, and have malignancies with potentially actionable variants for which no approved anticancer drugs are available. Here we show an overall rate of clinical benefit-defined as complete or partial response, or as stable disease beyond 16 weeks-of 34% in 215 treated patients, comprising 136 patients who received targeted therapies and 79 patients who received immunotherapy. The overall median duration of clinical benefit was 9 months (95% confidence interval of 8-11 months), including 26 patients who were experiencing ongoing clinical benefit at data cut-off. The potential of the Drug Rediscovery protocol is illustrated by the identification of a successful cohort of patients with microsatellite instable tumours who received nivolumab (clinical benefit rate of 63%), and a cohort of patients with colorectal cancer with relatively low mutational load who experienced only limited clinical benefit from immunotherapy. The Drug Rediscovery protocol facilitates the defined use of approved drugs beyond their labels in rare subgroups of cancer, identifies early signals of activity in these subgroups, accelerates the clinical translation of new insights into the use of anticancer drugs outside of their approved label, and creates a publicly available repository of knowledge for future decision-making.",
keywords = "CLINICAL-TRIALS, OPEN-LABEL, PHASE-II, RESPONSE ASSESSMENT, TARGETED THERAPY, 2-STAGE DESIGNS, MULTICENTER, CRITERIA, CANCERS, TUMORS",
author = "{van der Velden}, {D. L.} and Hoes, {L. R.} and {van der Wijngaart}, H. and Henegouwen, {J. M. van Berge} and {van Werkhoven}, E. and P. Roepman and Schilsky, {R. L.} and {de Leng}, {W. W. J.} and Huitema, {A. D. R.} and B. Nuijen and Nederlof, {P. M.} and {van Herpen}, {C. M. L.} and {de Groot}, {D. J. A.} and Devriese, {L. A.} and A. Hoeben and {de Jonge}, {M. J. A.} and M. Chalabi and Smit, {E. F.} and {de Langen}, {A. J.} and N. Mehra and M. Labots and E. Kapiteijn and S. Sleijfer and E. Cuppen and Verheul, {H. M. W.} and H. Gelderblom and Voest, {E. E.}",
note = "Funding Information: Acknowledgements We thank the Barcode for Life Foundation and the Dutch Cancer Society for their financial support; Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Merck Sharp and Dohme, Novartis, Pfizer and Roche for their in-kind and financial support; the HMF for their in-kind support by performing sequencing and biomarker analyses on baseline biopsies; the Center for Personalized Cancer Treatment Multidisciplinary Expert Board for supporting the central case-review process; the Independent Data Monitoring Committee for their advice on cohort decisions and the monitoring of preliminary safety data; the Netherlands Cancer Institute{\textquoteright}s Biobank Facility, Scientific Department and Pharmacy for their facilitating services; A. P. Hamberg, L. V. Beerepoot and J. M. Meerum-Terwogt for their contributions to trial recruitment; and all participating hospitals for supporting and facilitating the conduct of the DRUP trial. Funding Information: Competing interests E.E.V. is legally responsible for all contracts with pharmaceutical companies at the Netherlands Cancer Institute. H.M.W.V. and H.G. have, through the DRUP and other studies, received support from pharmaceutical companies that are participating in the DRUP. R.L.S serves as principal investigator for the TAPUR trial, in support of which the American Society of Clinical Oncology receives financial support from Astra-Zeneca, Bayer, Bristol-Myers Squibb, Genentech, Lilly, Merck and Pfizer. C.M.L.v.H. has received funding from AstraZeneca, BMS, Ipsen, Merck, MSD and Novartis. A.J.d.L. has served as an advisor for AstraZeneca, BMS, Boehringer, Pfizer, Lilly and MSD, and has received research grants from AstraZeneca, BMS and MSD. E.K. has served as advisor for Amgen, BMS, Eisai, Genzyme-Sanofi, MSD, Novartis and Roche. The other authors declare no competing interests. Funding Information: 32. Therasse, P. et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J. Natl. Cancer Inst. 92, 205–216 (2000). Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2019",
month = oct,
day = "3",
doi = "10.1038/s41586-019-1600-x",
language = "English",
volume = "574",
pages = "127--131",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7776",
}